EP0091309A2 - Composés de triazole comme fongicides - Google Patents
Composés de triazole comme fongicides Download PDFInfo
- Publication number
- EP0091309A2 EP0091309A2 EP83301894A EP83301894A EP0091309A2 EP 0091309 A2 EP0091309 A2 EP 0091309A2 EP 83301894 A EP83301894 A EP 83301894A EP 83301894 A EP83301894 A EP 83301894A EP 0091309 A2 EP0091309 A2 EP 0091309A2
- Authority
- EP
- European Patent Office
- Prior art keywords
- compound
- formula
- phenyl
- substituted
- pharmaceutically acceptable
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- 0 *C1(*[n]2ncnc2)O*1 Chemical compound *C1(*[n]2ncnc2)O*1 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
- C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
- C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
- C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
- C07D233/56—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
- C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
- C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
Definitions
- This invention relates to novel triazcle derivatives which have antifungal activity and are useful in the treatment of fungal infections in animals, including humans.
- Ar When Ar is a substituted phenyl group it may be substituted by from 1 to 3 substituents, each substituent being independently halo, CF 3 , C 1 -C 4 alkyl, C 1 -C 4 alkox y or C 1 -C 4 alkythio.
- a preferred substituted phenyl group Ar is dihalophenyl, especially 2,4-dichlorophenyl.
- the preferred biphenyl group is para-biphenyl.
- Halo means F, Cl, Br or I.
- Heterocyclic groups include 5 and 6 membered aromatic heterocyclic groups linked to the S(O) n group via a ring carbon atom.
- Particular examples include 2-imidazolyl, 2-thiazolyl, 3-(l,2,4-triazolyl), 5-tetrazolyl, 2-(1,3,4-thiadiazolyl), 2-, 3-and 4-pyridyl and 2- and 4-pyrimidinyl as well as benzo fused systems such as quinolyl and benzothiazolyl and biheterocyclic systems such as purinyl.
- Substituents for the heterocyclic or fused phenyl ring include one or more halo, CF 3 , C 1 -C 4 alkyl, C l- C 4 alkoxy, amino, mono or di C 1 -C 4 alkyl amino, alkanoylamino, hydroxy or thio groups.
- Preferred heterocyclic groups include imidazolyl, pyrimidinyl and thiazolyl, especially 2-imidazolyl, 2-(1-methyl-imidazolyl), 2-thiazolyl, and 2- and 4-pyrimidinyl.
- Alkyl, alkoxy and alkanoyl groups may be straight or branched chain where appropriate.
- the invention also provides a pharmaceutical composition
- a pharmaceutical composition comprising a compound of the formula (I) or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable diluent or carrier.
- the invention further provides a compound of the formula (I) or a pharmaceutically acceptable salt thereof, for use in treating fungal infections in animals, including humans.
- the compounds of formula (I) can be obtained by a number of different processes according to the invention.
- the compounds of the formula (I) in which n is 0 can be prepared from an oxirane of the formula: by reaction with a heterocyclic thiol of the formula: wherein Ar and Bet are as previously defined.
- the reaction can be achieved under a variety of different conditions, depending to some extent on the precise nature of the reactants. Generally it is possible to achieve the reaction in a convenient manner by simply heating the oxirane (II), as its free base, with excess of the heterocyclic thiol (III) in an organic solvent, e.g. dioxan. A period of up to three days at reflux temperature is generally sufficient, however addition of a catalytic amount of dilute sodium hydroxide solution often gives improved yields and reduces reaction times.
- the product can be isolated and purified by conventional procedures, for example by evaporating the solvent, taking the product up in a water immiscible organic solvent, extracting the product with dilute sodium hydroxide or potassium carbonate solution to remove unreacted thiol, drying and evaporating the solvent.
- the product may be further purified, if desired, by crystallisation or by chromatography.
- the oxirane as its methanesulphonate salt and the heterocyclic thiol are heated together in an organic solvent, e.g. N.N-dimethylformamide or tetrahydrofuran,in the presence of a base, e.g. potassium carbonate or sodium hydride.
- a base e.g. potassium carbonate or sodium hydride.
- a temperature of from 60 to 80°C is generally employed, and under these conditions the reaction is generally substantially complete within a few hours.
- the product is isolated and purified as previously described.
- the oxirane as its methanesulphonate salt is heated with excess of the heterocyclic thiol under reflux in glacial acetic acid for a period of several hours.
- the oxiranes (II) can be obtained by conventional methods, typically from the corresponding ketones (IV): by reaction with dimethyloxosulphonium methylide prepared from trimethylsulphoxonium iodide and either sodium hydride in dimethylsulphoxide or using cetrimide and sodium hydroxide in a mixture of water and toluene.
- the reaction using sodium hydride is typically achieved by adding dry powdered trimethylsulphoxonium iodide to a suspension of sodium hydride in dimethylsul phoxide. After stirring for, say, 30 minutes at room temperature, the ketone (IV) is added in an approximately equimolar amount in dimethylsulphoxide. The reaction mixture may be warmed to accelerate the reaction and after several hours at 50°-80°C, the product can be isolated by conventional procedures.
- the reaction utilising cetrimide is typically achieved by stirring the ketone (IV), trimethylsulphoxonium iodide and cetrimide vigorously together in a mixture of toluene and sodium hydroxide solution for about an hour at up to about 100°C.
- the oxirane product can then be isolated by conventional procedures.
- the ketones (IV) are either known compounds or can be prepared by procedures analogous to those of the prior art.
- the preparation of 2-(1H-1,2,4-triazol-1-yl)-2',4'-dichloroaceto- phenone from 2-bromo-2',4'dichloroacetophenone, 1,2,4-triazole and potassium carbonate is for example, described in Example 1 of British Patent Specification No. 1512918, which utilises acetonitrile as the solvent under reflux for 20 hours.
- this type of reaction is generally best carried out in acetone at 0-20°C, when it is generally complete in a shorter period of time, e.g. 4 hours or less.
- heterocyclic thiols of formula III are generally known compounds or they are prepared from readily available starting materials by conventional reactions.
- the preferred oxidizing agent is m-chloroperbenzoic acid: approximately one equivalent should be used to prepare the sulphoxides and an excess to prepare the sulphones.
- sulphoxide product of the oxidation which can be isolated by conventional procedures, will be a mixture of the two diastereoisoaers. If desired, the diastereoisomers can be separated by column chromatography, e.g. on silica, since they usually differ in polarity.
- the sulphones can be obtained simply by adding excess m-chloroperbenzoic acid to a solution of the crude sulphoxide, and stirring for a few hours, at room temperature. Alternatively the sulphones can be prepared by the oxidation of the thio compounds (n - 0) using excess m-chloroperbenzoic acid.
- acetylation reaction e.g.using acetic anhydride in pyridine
- Other transformation reactions and the conditions required for their performance will be well known to those skilled in the art.
- the sulphoxides of the formula (I) where n have two asymmetric centres, namely the carbon atom bearing the hydroxy group, and the sulphoxide sulphur atom. Consequently the sulphoxides exist in two diastereoisomeric forms, each of which is a racemate consisting of a pair of enantiomers.
- the two diastereoisomeric pairs can be readily separated by column chromatography, since they differ markedly in polarity. Each diastereoisomeric pair can be resolved further into its individual optically active enantiomers by techniques known to those skilled in the art. In some cases, one diastereoisomeric pair may predominate over the other.
- the invention includes each diastereoisomeric pair whether resolved or not.
- All the compounds of the invention contain at least one chiral centre, and the invention includes both resolved and unresolved forms.
- Pharmaceutically acceptable acid addition salts of the compounds of the formula (I) include those formed from strong acids which form non-toxic acid addition salts, such as hydrochloric, hydrobromic, sulphuric, nitric, oxalic and methanesulphonic acids.
- the salts may be obtained by conventional procedures, e.g. by mixing solutions containing equimolar amounts of the free base and desired acid, and the required salt is collected by filtration, if insoluble, or by evaporation of the solvent.
- the compounds of the formula (I) and their pharmaceutically acceptable salts are anti-fungal agents, useful in combating fungal infections in animals, including humans.
- they are useful in treating topical fungal infections in man caused by, among other organisms, species of Candida, Trichophyton, Microsporum, or Epidermophyton, or in mucosal infections caused by Candida albicans (e.g. thrush and vaginal candidiasis).
- They may also be used systemically in the treatment of systemic fungal infections caused by, for example, Candida albicans, Cryptococcus neoformans, Aspergillus fumigatus, Coccidioides, Paracoccidioides, Histoplasma or Blastomyces.
- the in vitro evaluation of the anti-fungal activity of the compounds can be performed by determining the minimum inhibitory concentration (m.i.c.) of the test compounds in a suitable medium at which growth of the particular micro-organism fails to occur.
- m.i.c. minimum inhibitory concentration
- a series of agar plates, each having the test compound incorporated at a particular concentration are inoculated with a standard culture of, for example, Candida albicans and each plate is then incubated for 48 hours at 37°C. The plates are then examined for the presence or absence of growth of the fungus and the appropriate m.i.c. value is noted.
- micro-organisms used in such tests can include Cryptococcus neoformans, Aspergillus fumigatus, Trichophyton spp; Microsporum spp; E p idermophyton floccosum, Coccidioicds immitis, and Torulopsis glabrata.
- the in vivo evaluation of the compounds can be carried out at a series of dose levels by intraperitoneal or intravenous injection or by oral administration, to mice which are inoculated with a strain of Candida albicans. Activity is based on the survival of a treated group of mice after the death of an untreated group of mice following 48 hours observation. The dose level at which the compound provides 50% protection against the lethal effect of the infection is noted.
- the anti-fungal compounds of the formula (I) can be administered alone, but will generally be administered in admixture with a pharmaceutical carrier selected with regard to the intended route of administration and standard pharmaceutical practice.
- a pharmaceutical carrier selected with regard to the intended route of administration and standard pharmaceutical practice.
- they may be administered orally in the form of tablets containing such excipients as starch or lactose, or in capsules or ovules either alone or in admixture with excipients, or in the form of elixirs or suspensions containing flavouring or colouring agents.
- They may be injected parenterally, for example, intravenously, intramuscularly or subcutaneously.
- parenteral administration they are best used in the form of a sterile aqueous solution which may contain other substances, for example, enough salts or glucose to make the solution isotonic.
- the daily dosage level of the anti-fungal compounds of the formula (I) will be from 0.1 toJOmg/kg (in divided doses) when administered by either the oral or parenteral route.
- tablets or capsules of the compounds can be expected to contain from 5 mg to 0.5 g of active compound for administration singly or two or more at a time as appropriate.
- the physician in any event will determine the actual dosage which will be most suitable for an individual patient and it will vary with the age, weight and response of the particular patient.
- the above dosages are exemplary of the average case. There can, of course, be individual instances where higher or lower dosage ranges are merited, and such are within the scope of this invention.
- the anti-fungal compounds of formula (I) may be administered in the form of a suppository or pessary, or they may be applied topically in the form of a lotion, solution, cream, ointment or dusting powder.
- they may be incorporated into a cream consisting of an aqueous emulsion of polyethylene glycols or liquid paraffin; or they may be incorporated, at a concentration between 1 and 10%, into an ointment consisting of a white wax or white soft paraffin base together with such stabilizers and preservatives as may be required.
- the compounds are also useful as agricultural fungicides for treating plants and seeds to eradicate or prevent fungal infections.
- Example 23 The procedure of Example 23 was followed but starting with 1-[2-(2,4-dichlorophenyl)-2-hydroxy-3-(-4,5-dimethyl-thiazol-2- ylthio)propyl]-1,2,4-triazole (250 mg) to yield the title sulphoxide (isomer 1) 20 mg 8X. m.p. 199-200°C.
- Sodium hydride (3.78 g, 0.079 mole as 50% dispersion in oil) was suspended, with stirring, in 20 ml of dry diethyl ether. The ether was then removed by decantation, and the sodium hydride was dried in a stream of dry nitrogen. 100 Ml of dry dimethyl sulphoxide was added followed by 17.34 (0.079 mole) of dry powdered trimethylsulphoxonium iodide, in portions, over 15 minutes. The resulting mixture was stirred for 30 minutes at room temperature (20°C).
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Communicable Diseases (AREA)
- Pharmacology & Pharmacy (AREA)
- Oncology (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
GB8210312 | 1982-04-07 | ||
GB8210312 | 1982-04-07 |
Publications (3)
Publication Number | Publication Date |
---|---|
EP0091309A2 true EP0091309A2 (fr) | 1983-10-12 |
EP0091309A3 EP0091309A3 (en) | 1985-04-03 |
EP0091309B1 EP0091309B1 (fr) | 1987-10-28 |
Family
ID=10529582
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
EP83301894A Expired EP0091309B1 (fr) | 1982-04-07 | 1983-04-05 | Composés de triazole comme fongicides |
Country Status (7)
Country | Link |
---|---|
US (1) | US4678789A (fr) |
EP (1) | EP0091309B1 (fr) |
JP (1) | JPS58189173A (fr) |
DE (1) | DE3374197D1 (fr) |
DK (1) | DK157135C (fr) |
GR (1) | GR78172B (fr) |
IE (1) | IE54972B1 (fr) |
Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4631288A (en) * | 1983-09-23 | 1986-12-23 | Bayer Aktiengesellschaft | Triazolylmethyl-pyridyloxymethyl-carbinol fungicides |
US4638007A (en) * | 1983-08-26 | 1987-01-20 | Pfizer Inc. | Triazole antifungal agents |
WO1995025107A1 (fr) * | 1994-03-12 | 1995-09-21 | Yuhan Corporation | Composes triazoliques et leurs procedes de preparation |
Families Citing this family (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5021574A (en) * | 1988-03-03 | 1991-06-04 | Ortho Pharmaceutical Corporation | 6-substituted purinyl piperazine derivatives |
US4876257A (en) * | 1988-03-03 | 1989-10-24 | Ortho Pharmaceutical Corporation | 6-Substituted purinyl piperazine derivatives useful as cardiotonic and antiarrhythmic agents |
US5164390A (en) * | 1988-03-03 | 1992-11-17 | Ortho Pharmaceutical Corporation | 6-substituted purinyl piperazine derivatives |
IE903395A1 (en) * | 1989-09-26 | 1991-04-10 | Takeda Chemical Industries Ltd | Triazole compounds, their production and use |
TW206224B (fr) * | 1989-12-14 | 1993-05-21 | Takeda Pharm Industry Co Ltd | |
JPH05262764A (ja) * | 1992-01-24 | 1993-10-12 | Morishita Roussel Kk | 1−アリール−2−(1h−1,2,4−トリアゾー ル−1−イル)エタノール誘導体 |
Citations (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0015756A1 (fr) * | 1979-03-07 | 1980-09-17 | Imperial Chemical Industries Plc | Composés triazoliques, procédé pour leur préparation, leur application comme fongicides pour les plantes et compositions fongicides les contenant |
EP0043419A1 (fr) * | 1980-05-16 | 1982-01-13 | Bayer Ag | Composition antimycotique |
EP0044605A1 (fr) * | 1980-06-02 | 1982-01-27 | Imperial Chemical Industries Plc | Composés bis-azolyls fongicides |
EP0046633A1 (fr) * | 1980-08-22 | 1982-03-03 | Imperial Chemical Industries Plc | Composés hétérocycliques utilisés comme pesticides et leur procédé de préparation |
EP0047594A2 (fr) * | 1980-08-18 | 1982-03-17 | Imperial Chemical Industries Plc | Dérivés de triazole, leur procédé de préparation, leur utilisation comme fongicides et régulateurs de croissance des plantes |
EP0054974A1 (fr) * | 1980-12-24 | 1982-06-30 | Sumitomo Chemical Company, Limited | Dérivés de l'imidazolylpropanole et leurs sels d'addition avec un acide, procédé de préparation et leur utilisation |
EP0061835A1 (fr) * | 1981-03-18 | 1982-10-06 | Imperial Chemical Industries Plc | Composés de triazole , procédé pour leur préparation, leur utilisation comme fongicides de plantes et leurs compositions fongicides |
Family Cites Families (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE3000244A1 (de) * | 1980-01-05 | 1981-07-09 | Bayer Ag, 5090 Leverkusen | Triazolylphenacyl-pyridyl-ether-derivate, verfahren zu ihrer herstellung sowie ihre verwendung als fungizide |
-
1983
- 1983-02-28 DK DK098383A patent/DK157135C/da not_active IP Right Cessation
- 1983-03-28 US US06/479,525 patent/US4678789A/en not_active Expired - Lifetime
- 1983-04-05 DE DE8383301894T patent/DE3374197D1/de not_active Expired
- 1983-04-05 EP EP83301894A patent/EP0091309B1/fr not_active Expired
- 1983-04-06 IE IE773/83A patent/IE54972B1/en not_active IP Right Cessation
- 1983-04-06 GR GR71014A patent/GR78172B/el unknown
- 1983-04-07 JP JP58061497A patent/JPS58189173A/ja active Granted
Patent Citations (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0015756A1 (fr) * | 1979-03-07 | 1980-09-17 | Imperial Chemical Industries Plc | Composés triazoliques, procédé pour leur préparation, leur application comme fongicides pour les plantes et compositions fongicides les contenant |
EP0043419A1 (fr) * | 1980-05-16 | 1982-01-13 | Bayer Ag | Composition antimycotique |
EP0044605A1 (fr) * | 1980-06-02 | 1982-01-27 | Imperial Chemical Industries Plc | Composés bis-azolyls fongicides |
EP0047594A2 (fr) * | 1980-08-18 | 1982-03-17 | Imperial Chemical Industries Plc | Dérivés de triazole, leur procédé de préparation, leur utilisation comme fongicides et régulateurs de croissance des plantes |
EP0046633A1 (fr) * | 1980-08-22 | 1982-03-03 | Imperial Chemical Industries Plc | Composés hétérocycliques utilisés comme pesticides et leur procédé de préparation |
EP0054974A1 (fr) * | 1980-12-24 | 1982-06-30 | Sumitomo Chemical Company, Limited | Dérivés de l'imidazolylpropanole et leurs sels d'addition avec un acide, procédé de préparation et leur utilisation |
EP0061835A1 (fr) * | 1981-03-18 | 1982-10-06 | Imperial Chemical Industries Plc | Composés de triazole , procédé pour leur préparation, leur utilisation comme fongicides de plantes et leurs compositions fongicides |
Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4638007A (en) * | 1983-08-26 | 1987-01-20 | Pfizer Inc. | Triazole antifungal agents |
US4631288A (en) * | 1983-09-23 | 1986-12-23 | Bayer Aktiengesellschaft | Triazolylmethyl-pyridyloxymethyl-carbinol fungicides |
WO1995025107A1 (fr) * | 1994-03-12 | 1995-09-21 | Yuhan Corporation | Composes triazoliques et leurs procedes de preparation |
Also Published As
Publication number | Publication date |
---|---|
US4678789A (en) | 1987-07-07 |
IE830773L (en) | 1983-10-07 |
DE3374197D1 (en) | 1987-12-03 |
DK157135C (da) | 1990-04-02 |
GR78172B (fr) | 1984-09-26 |
DK157135B (da) | 1989-11-13 |
DK98383D0 (da) | 1983-02-28 |
DK98383A (da) | 1983-10-08 |
EP0091309A3 (en) | 1985-04-03 |
JPS58189173A (ja) | 1983-11-04 |
IE54972B1 (en) | 1990-04-11 |
JPS6320432B2 (fr) | 1988-04-27 |
EP0091309B1 (fr) | 1987-10-28 |
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